PROJECT SUMMARY Thoracic aortic aneurysms (TAAs) affect young and old males and females and are responsible for significant morbidity and mortality. Findings over recent years suggest that an aberrant activity of or signaling through transforming growth factor-beta (TGF?) plays important roles in TAAs, yet controversy remains regarding the precise mechanisms. This lack of understanding continues to hinder the identification of improved therapeutic approaches as revealed by the recent failure of a highly anticipated clinical trial of losartan, an angiotensin-II receptor antagonist. We and others recently hypothesized that the collection of predisposing genetic mutations suggests that TAAs result from a compromised cellular mechanosensing and mechanoregulation of the extracellular matrix that endows the aortic wall with its structural integrity. Importantly, TGF? can be viewed, in part, as an important mechanotransducer ? its production and activation are mechanosensitive and its downstream gene products include the contractile proteins that are fundamental to sensing and regulating the extracellular matrix that is produced in response to its increased signaling. The goal of our work is to test novel hypotheses on interactions among the structural and instructional roles of altered TGF? signaling, smooth muscle cell mechanosensing of altered wall stresses (particularly those due to hypertension, a primary risk factor for TAAs), and the integrity of fibrillin-1, an essential glycoprotein that associates with elastin to form elastic fibers. Towards this end, we will use a combination of new genetically modified mouse models, in vivo models of induced hypertension, and clinical specimens of TAAs. Specifically, we will characterize responses of smooth muscle cells in the thoracic aorta to increased wall stresses and disrupted fibrillin-1 that depend on TGF? signaling and lead to maladaptive remodeling of the aortic wall. The results of our work will thereby provide the first mechanistic investigation of roles of TGF? signaling in cases of hypertension (a major risk factor for TAAs) and compromised extracellular matrix (fibrillin-1, the cause of the majority of syndromic TAAs) while testing, for the first time, the recently proposed hypothesis that dysfunctional smooth muscle mechanosensing and mechanoregulation of matrix underlies many different causes of TAAs. In particular, we suggest that smooth muscle cells will invoke an atrophic process if they sense stresses lower than homeostatic even in cases wherein the actual stress is normal or higher than normal, which will drive the wall toward aneurysmal development. The characterization of TGF?-dependent mechanoresponses by aortic smooth muscle cells may identify new molecular targets to treat TAAs, a lethal disease and without current pharmacotherapy.